PHCCC, a specific enhancer of type 4 metabotropic glutamate receptors, reduces proliferation and promotes differentiation of cerebellar granule cell neuroprecursors
PHCCC, a specific enhancer of type 4 metabotropic glutamate receptors, reduces proliferation and promotes differentiation of cerebellar granule cell neuroprecursors
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DOI：
10.1523/jneurosci.3229-04.2004
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发表时间：
2004-11-17
影响因子：
5.3
通讯作者：
Melchiorri, D
中科院分区：
文献类型：
--
作者：
Canudas, AM;Di Giorgi-Gerevini, V;Melchiorri, D
未成熟大鼠小脑颗粒细胞培养物暴露于4型代谢型谷氨酸（mGlu 4）受体增强剂N-苯基-7-（羟亚氨基）环丙烯[B]色烯-1a-甲酰胺（PHCCC）减少[H-3]胸苷掺入。它的行动是敏感的生长条件和衰减的两个mGlu 4受体拮抗剂。PHCCC的抗增殖作用也见于野生型，但不是mGlu 4，敲除小鼠的文化。至少在大鼠培养物中，PHCCC没有神经毒性，并增强了轴突发生。虽然PHCCC减少cAMP的形成和磷酸化AKT水平的增加引起的毛喉素，这些转导途径显着减少[H-3]胸苷掺入。有趣的是，PHCCC降低了Gli-1的表达，Gli-1是一种介导Sonic hedgehog促有丝分裂作用的转录因子。最后，我们用PHCCC脑内（在小脑区域每隔一天输注5 nmol/2穆尔）或全身（5 mg/kg，i. p.，每天一次）。局部灌注PHCCC引起发育中小脑形态的显著变化。与此相反，全身注射PHCCC只引起小脑小叶V的形态异常，这在治疗结束后11天变得可见。这些数据表明mGlu 4受体参与了小脑发育的调节。
Exposure of immature rat cerebellar granule cell cultures to the type 4 metabotropic glutamate (mGlu4) receptor enhancer N-phenyl-7-(hydroxyimino) cyclopropa[b] chromen-1a-carboxamide (PHCCC) reduced [H-3] thymidine incorporation. Its action was sensitive to the growth conditions and was attenuated by two mGlu4 receptor antagonists. An antiproliferative action of PHCCC was also seen in cultures from wild-type, but not mGlu4, knock-out mice. At least in rat cultures, PHCCC was not neurotoxic and enhanced neuritogenesis. Although PHCCC reduced the increase in cAMP formation and phospho-AKT levels induced by forskolin, none of these transduction pathways significantly contributed to the reduction of [H-3] thymidine incorporation. Interestingly, PHCCC reduced the expression of Gli-1, a transcription factor that mediates the mitogenic action of Sonic hedgehog. Finally, we treated newborn rats with PHCCC either intracerebrally (infusion of 5 nmol/2 mul in the cerebellar region once every other day) or systemically (5 mg/kg, i.p., once daily) from postnatal days 3-9. Local infusion of PHCCC induced substantial changes in the morphology of the developing cerebellum. In contrast, systemic injection of PHCCC induced only morphological abnormalities of the cerebellar lobule V, which became visible 11 d after the end of the treatment. These data suggest that mGlu4 receptors are involved in the regulation of cerebellar development.